Over 40 diseases have been shown to be associated with human leukocyte (HLA) antigens of the major histocompatibility complex in humans. Theoretical studies in the development of models to determine the modes of inheritance of the HLA associated diseases have led to a better understanding of the inheritance pattern in insulin dependent diabetes mellitus, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, hemochromatosis, celiac disease, and others. It is now clear that the HLA associated diseases may involve heterogeneity in their HLA components, as well as non-HLA genetic components. The specific aim of our research program is to study the genetic and environmental components in the etiology of the HLA associated diseases, and population genetic features of the HLA region. Our research approach will involve the development of novel methods based on mathematical and genetic- epidemiological models to analyze population and family data, including the construction of statistical analyses that can test the various models. Our disease studies will include investigation of the extent of heterogenity and modes of inheritance of the HLA associated disease predisposing alleles, the contribution of non- HLA loci to the genetic component of the HLA associated diseases, the contribution of non-genetic components to disease expression, the role of the HLA antigens themselves in disease predisposition, the genetic interrelationship of the HLA associate ddiseases, and the analysis of restriction fragment length polymorphism (RFLP) data for the HLA associated diseases. Our population studies will continue our theoretical studies of measures of linkage disequilibrium and analysis of HLA population data, including the RFLP data. The great variety and complexity of molecular, genetic and physiological phenomena present in the expression of the genes of the HLA region make it an extraordinary resource and testing ground for examining genetic causation in disease. The results of our studies have profound public health significance, particularly in the application of screening health programs and genetic counseling, and bear considerably on new approaches relating to recombinant DNA technologies and gene therapy, differential diagnosis and epidemiological considerations.